RU2727515C2 - Compositions for oral care - Google Patents

Abstract

FIELD: hygiene; pharmaceutics.SUBSTANCE: invention relates to novel aqueous compositions for oral care. Described is an oral care composition containing: a) an acidic polymer acceptable for oral use, comprising a combination of: i) copolymers with ratio of 1:4 to 4:1, maleic anhydride or maleic acid with another ethylenically unsaturated monomer capable of polymerisation, for example copolymers of methyl vinyl ether and maleic anhydride, where some or all anhydride fragments are hydrolysed to provide free carboxyl groups; and ii) copolymerized products of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1,, where n equals 0, 1 or 2; b) a non-ionogenic polymer acceptable for oral use, wherein the non-ionogenic polymer acceptable for oral use is selected from polyethylene glycols, polypropylene glycols, poloxamers and mixtures thereof; c) an effective amount of a cationic active acceptable for oral use, in a free form or form acceptable for use in the oral cavity of the salt, where the cationic active agent acceptable for oral use is selected from one or more quaternary ammonium surfactants, biguanides, cationic amino acids, metal cations, their combinations; d) a stabilizing amount of the compound, which is a polyamine, in a free form or a form acceptable for use in the oral cavity of the salt, where the polyamine is lysine; e) sodium lauryl sulphate and f) water.EFFECT: technical result is creation of new compositions for oral care and methods, which can prevent coloration and/or formation of biofilm.14 cl, 16 tbl, 2 ex

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application claims priority under Provisional US Patent Application Serial No. 62/261791, filed December 1, 2015, which is incorporated herein by reference in its entirety.

LEVEL OF TECHNOLOGY

[0002] The present application, inter alia, relates to new aqueous oral compositions suitable for combining and delivering poorly compatible ingredients, for example, to deliver effective levels of cationic antibacterial agents in combination with polymers that provide erosion and stain protection.

[0003] Biofilms form when bacteria adhere to surfaces in some form of aqueous medium and begin to secrete a viscous, sticky substance that can adhere to all types of materials - metals, plastics, soil particles, medical implant materials, biological tissues. Plaque is a biofilm that adheres to the surface of the tooth and other surfaces of the oral cavity, in particular to the gingival margin, and leads to gingivitis, periodontitis, caries, and other forms of periodontal disease. Plaque is cohesive and highly resistant to removal from teeth and / or oral surfaces. The bacteria associated with plaque convert sugars into glucans, which are insoluble polysaccharides that give plaque its cohesive properties. The anaerobic bacteria in the plaque metabolize sugar to produce acids that dissolve the minerals of the tooth, damaging the enamel and ultimately promoting dental caries. Saliva can neutralize acids produced by bacteria and help remineralize enamel, however, significant plaque can block saliva from contacting enamel. The re-deposition of minerals in the biofilm forms hard deposits on the tooth called calculus (or tartar), which become a local irritant to the gums, causing gingivitis.

[0004] Various antibacterial agents can slow down the growth of bacteria and, thus, reduce the degree of biofilm formation on the surfaces of the oral cavity. In many cases, such antibacterial agents are cationic, such as quaternary ammonium surfactants such as cetylpyridinium chloride (CPC), biguanides such as chlorhexidine, metal cations such as zinc or stannous ions, and guanidines such as arginine ...

[0005] Daily activities such as smoking or other use of tobacco products in the mouth, as well as the consumption, chewing or drinking of certain foods and drinks (in particular coffee, tea, cola drinks and red wine), cause unwanted staining of tooth surfaces ... Staining can also result from microbial activity, including those associated with plaque formation. Chromogens or color-giving substances in such materials become part of the plaque layer on the tooth surface and can penetrate into the enamel layer. Even with regular brushing and flossing, years of chromogen buildup can lead to noticeable discoloration of teeth.

[0006] The tooth consists of an inner dentin layer and an outer hard enamel layer, which is the protective layer of the tooth. The enamel layer of a tooth in its natural state is opaque and is white or white with a slight tint. The enamel layer consists of crystals of the mineral substance hydroxyapatite, which form a somewhat porous surface. These hydroxyapatite crystals form microscopic hexagonal rods or prisms that make up the enamel surface. As a result, microscopic spaces or pores between the prisms are presented on the enamel surface. Without limiting the mechanism, function, or usefulness of the present invention, it is believed that the porous nature of the enamel is such that the color-changing substances penetrate the enamel and discolor the teeth.

[0007] Since the compounds that stain teeth are usually anionic materials, cationic antibacterial agents can induce or enhance staining by facilitating the deposition of chromogens or through the formation of salts with minerals.

[0008] One approach to reduce the intensity of staining and erosion, as well as to reduce the formation of biofilm uses anionic polymers that help to coat and protect the enamel, preventing the attachment of bacteria and repelling chromogens. Such polymers, however, can interact with cationic antimicrobial agents, resulting in formulation incompatibilities, in particular in high water formulations such as mouthwashes, and interferes with delivery of the antimicrobial agent and / or polymer. Oral care products containing such polymers are disclosed, for example, in WO 2015094336 A1, which is incorporated herein by reference.

[0009] Thus, there is a need for new oral compositions and methods that can inhibit staining and / or biofilm formation.

BRIEF DESCRIPTION OF THE INVENTION

[0010] Surprisingly, it has been found that the addition of a stabilizing amount of an orally acceptable polyamine compound such as lysine to formulations containing an anionic polymer and a cationic antibacterial agent inhibits the binding of these components and enhances delivery to the teeth.

[0011] In certain embodiments, the compositions may form an unusual aqueous biphasic system where the cationic agent is concentrated in a single phase. When the phases are mixed, such as by shaking before use, the cationic agent is delivered in microdroplets having a very high concentration of active, thus providing improved delivery and a high local concentration of the active at the delivery site compared to a uniform solution of the cationic agent. These formulations differ from traditional two-phase formulations in which both phases are aqueous and not one phase is hydrophobic but the other is hydrophilic. They also differ from structured compositions such as gels in that they separate into phases having different compositions and densities, such as an upper phase and a lower phase, which can be easily mixed by shaking and which will then re-separate within a short period of time.

[0012] For example, cetylpyridinium chloride (CPC) is generally incompatible with anionic polymers due to the resulting precipitation of both components. The addition of lysine provides the necessary stability and competition between acidic functional groups of the polymer, acidic and amine functional groups of lysine and CPC, the result is the release of CPC and making it more accessible for interaction with bacteria. In some embodiments, the addition of glutamic acid further improves CPC availability through additional competitive pathways involving the carboxy groups of glutamic acid. Without lysine (and optionally glutamic acid), a CPC and anionic polymer formulation may perform slightly better than a non-CPC material or medium control.

[0013] Likewise, chlorhexidine will generally complex with anionic polymers no matter what steps are taken given their high charge density and entropy-controlled precipitation reaction. However, the inventors have found that chlorhexidine and anionic polymers can be formulated to prevent precipitation (or to re-enter the solution) by including lysine (Lys), polyethylene glycol (PEG) and low levels of anionic surfactant, such as sodium lauryl sulfate (SLS). An additional nonionic surfactant, such as poloxamer, can be used to supplement the SLS proportion.

[0014] Thus, in one embodiment, the present invention provides oral compositions comprising

(i) an orally acceptable acidic polymer, for example a polymer having an isoelectric pH point less than 5, for example selected from one or more (a) synthetic anionic linear polycarboxylates, such as copolymers in a ratio of 1: 4 to 4 : 1, maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer, for example copolymers of methyl vinyl ether and maleic anhydride, where some or all of the anhydride moieties are hydrolyzed to provide free carboxyl groups, and (b) copolymers of phosphate and acrylate, for example polymer from acrylate monomers and monomers bearing phosphate groups, for example a copolymerized product of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1,

where n is 0, 1 or 2; and mixtures thereof; for example, wherein the orally acceptable acidic polymer has a molecular weight of at least 7,500 Da, such as 10 kDa to 1500 kDa;

(ii) an orally acceptable nonionic polymer, for example, selected from one or more poly (alkylene oxide) polymers, for example selected from polyethylene glycols, polypropylene glycols, poloxamers, and mixtures thereof; for example, where an acceptable for use in the oral cavity nonionic polymer has a molecular weight of at least 3000 Da, for example, from 6 kDa to 250 kDa;

(iii) an effective amount of an orally acceptable cationic active agent, in free form or an orally acceptable salt form, for example selected from one or more quaternary ammonium surfactants (such as cetylpyridinium chloride (CPC )), biguanides (such as chlorhexidine bigluconate), cationic amino acids (such as arginine), metal cations (such as zinc, calcium or stannous ions), or combinations thereof;

(iv) a stabilizing amount of a polyamine, for example having an isoelectric point of pH greater than 8.5, for example lysine, for example, which can be added in free or salt form; and

(v) water.

[0015] The present invention further provides methods for preventing erosion, staining and / or biofilm formation on teeth, comprising administering the described composition to the oral cavity.

[0016] Additional areas of application of the present invention will become apparent from the detailed description provided later in this document. It should be understood that while the detailed description and specific examples disclose a preferred embodiment of the present invention, they are intended for illustrative purposes only and are not intended to limit the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The following description of the preferred embodiment (s) is illustrative only and is in no way intended to limit the present invention, its practical application or uses.

[0018] Used throughout this application, the ranges are used as an abbreviation to describe each individually value that is within the range. Any value within the range can be selected as the limit value of the range. In addition, all references in this document are hereby incorporated by reference in their entirety. In the event of a conflict of definitions in the description of the present invention and in the description of the cited reference, the description of the present invention shall prevail.

[0019] Unless otherwise indicated, all percentages and amounts stated herein and elsewhere in this specification are to be understood as referring to percentages by weight. The quantities quoted are based on the active weight of the material.

[0020] As is generally accepted in the art, the compositions described herein are sometimes described with respect to their ingredients, although the ingredients may dissociate, associate, or react in the composition. For example, ions are typically formulated in the form of a salt, which can dissolve and dissociate in aqueous solution. It should be understood that the present invention covers both the mixture of the described ingredients and the product thus obtained.

[0021] In a first embodiment, the present invention provides oral compositions (composition 1) comprising

(i) an orally acceptable acidic polymer;

(ii) an orally acceptable nonionic polymer;

(iii) an effective amount of an orally acceptable cationic active agent in free form or an orally acceptable salt form;

(iv) a stabilizing amount of lysine or polylysine, in free form or in an orally acceptable salt form; and

(v) water.

[0022] For example, the following embodiments of Composition 1 are provided in the present invention.

1.1. Composition 1, wherein the orally acceptable acidic polymer is in linear or branched form or mixtures thereof, characterized by acidic functional groups to provide an isoelectric pH point of 5 or less, and optionally additionally having uncharged spacers or side chains, for example containing hydrophobic moieties (such as methyl methacrylate monomers or alkane chains); and / or uncharged hydrophilic moieties (such as polyalkylene glycols).

1.2. Composition 1, wherein the orally acceptable acidic polymer is selected from one or more synthetic anionic linear polycarboxylates, copolymers of phosphate and acrylate, and combinations thereof.

1.3. Composition 1 or 1.1, wherein the orally acceptable acidic polymer is selected from one or more (a) copolymers in a ratio of 1: 4 to 4: 1, maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer, for example copolymers of methyl vinyl ether and maleic anhydride, where some or all of the anhydride moieties are hydrolyzed to provide free carboxyl groups, and (b) copolymerized products of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1,

where n is 0, 1 or 2; and mixtures thereof;

for example, wherein an orally acceptable acidic polymer has a molecular weight of at least 7,500 Da, such as 10 kDa to 1500 kDa.

1.4. Any of the foregoing compositions wherein the orally acceptable acidic polymer comprises a phosphate-acrylate copolymer, which is a copolymerized product of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of Formula 1,

where n is 0, 1, or 2.

1.5. Any of the above composition, wherein the orally acceptable acidic polymer comprises a phosphate-acrylate copolymer, wherein the phosphate-acrylate copolymer is a copolymerized product of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1 containing acrylic acid in a molar percentage concentration , constituting 80-90%, for example approximately 85%; methacrylic acid in a molar percentage of 5-15%, for example about 11%, and hydroxyethyl methacrylate phosphates of formula 1 in a molar percentage of 2-6%, for example about 4%.

1.6. Any of the foregoing compositions wherein the orally acceptable acidic polymer comprises a phosphate-acrylate copolymer, wherein the phosphate-acrylate copolymer has an average molecular weight of 10 to 40 kDa, for example 20 to 30 kDa.

1.7. Any composition above wherein the orally acceptable acidic polymer comprises a phosphate / acrylate copolymer, wherein the acid phosphate / acrylate copolymer is a random copolymer having a weight average molecular weight of about 20,000 to 30,000 grams per mole, which is the copolymerized blend product acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1, for example, in a molar ratio of about 85: 11: 4.

1.8. Any of the above composition, where an acidic polymer acceptable for use in the oral cavity contains from 0.1 to 10 wt. % of a copolymer of phosphate and acrylate, for example from 0.2 to 9 wt. % of a copolymer of phosphate and acrylate, for example from 0.3 to 8 wt. % of a copolymer of phosphate and acrylate, for example from 0.4 to 7 wt. % of a copolymer of phosphate and acrylate, for example from 0.5 to 6 copolymer of phosphate and acrylate, for example, from 0.5 to 5 wt. % of a copolymer of phosphate and acrylate, for example from 0.5 to 4 wt. % of a copolymer of phosphate and acrylate, for example from 0.5 to 3 wt. % of a copolymer of phosphate and acrylate, for example from 0.5 to 2 wt. % copolymer of phosphate and acrylate, for example from 1 to 10 wt. % of a copolymer of phosphate and acrylate, for example from 1 to 8 wt. % copolymer of phosphate and acrylate, for example from 1 to 6 wt. % copolymer of phosphate and acrylate, for example from 1 to 5 wt. % copolymer of phosphate and acrylate, for example from 1 to 4 wt. % copolymer of phosphate and acrylate, for example from 1 to 3 wt. % copolymer of phosphate and acrylate, for example from 1 to 2 wt. % copolymer of phosphate and acrylate.

1.9. Any of the above composition, where an acidic polymer acceptable for use in the oral cavity contains from 0.01 to 30 weight. % synthetic anionic linear polycarboxylate, for example from 0.1 to 30 wt. % synthetic anionic linear polycarboxylate, for example from 1 to 30 wt. % synthetic anionic linear polycarboxylate, for example from 5 to 30 wt. % synthetic anionic linear polycarboxylate, for example from 10 to 30 wt. % synthetic anionic linear polycarboxylate, for example from 10 to 20 wt. % synthetic anionic linear polycarboxylate, for example 15 wt. % synthetic anionic linear polycarboxylate, for example 17 wt. % synthetic anionic linear polycarboxylate.

1.10. Any of the foregoing compositions wherein the orally acceptable acidic polymer comprises a copolymer of maleic anhydride and methyl vinyl ether.

1.11. Any of the foregoing compositions wherein an orally acceptable acidic polymer comprises a copolymer in a ratio of 1: 4 to 4: 1, methyl vinyl ether and maleic anhydride (optionally fully or partially hydrolyzed after copolymerization to give the corresponding acid).

1.12. Any of the foregoing compositions, wherein an orally acceptable acidic polymer comprises a copolymer in a ratio of 1: 4 to 4: 1, methyl vinyl ether and maleic anhydride (optionally fully or partially hydrolyzed after copolymerization to give the corresponding acid) with a molecular weight of ( MW) ranging from about 30,000 to about 1,000,000, for example from about 300,000 to about 800,000.

1.13. Any of the foregoing compositions wherein the orally acceptable acidic polymer comprises a combination of maleic anhydride methyl vinyl ether copolymer and acrylate phosphate copolymer.

1.14. Any of the foregoing compositions wherein an orally acceptable acidic polymer comprises a combination of (i) a copolymer of maleic anhydride and methyl vinyl ether and (ii) a copolymer of phosphate and acrylate in a weight ratio of about 1: 1.

1.15. Any of the foregoing compositions wherein the orally acceptable acidic polymer comprises 0.5% to 2% maleic anhydride methyl vinyl ether copolymer and 0.5% to 2% phosphate acrylate copolymer.

1.16. Any composition above wherein the orally acceptable acidic polymer comprises a combination of (i) a copolymer in a ratio of 1: 4 to 4: 1, methyl vinyl ether and maleic anhydride (optionally wholly or partially hydrolyzed after copolymerization to give the corresponding acid) with a molecular weight (MW) ranging from about 30,000 to about 1,000,000, such as from about 300,000 to about 800,000; and (ii) a copolymer of phosphate and acrylate, where the copolymer of phosphate and acrylate is a copolymerized product of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of Formula 1, containing acrylic acid in a molar percentage of 80-90%, for example about 85 %; methacrylic acid in a molar percentage of 5-15%, for example about 11%, and hydroxyethyl methacrylate phosphates of formula 1 in a molar percentage of 2-6%, for example about 4%.

1.17. Any composition above wherein the orally acceptable acidic polymer is present in a total amount of 1% to 3%.

1.18. Any of the above composition wherein the orally acceptable nonionic polymer is selected from one or more poly (alkylene oxide) polymers.

1.19. Any of the foregoing compositions wherein the orally acceptable nonionic polymer is selected from polyethylene glycols, polypropylene glycols, poloxamers, polyethylene glycol and polypropylene glycol copolymers, and mixtures thereof.

1.20. Any of the foregoing compositions wherein an orally acceptable nonionic polymer has a molecular weight of at least 3000 Da, eg, 6 kDa to 250 kDa.

1.21 Any of the foregoing compositions wherein the orally acceptable nonionic polymer is selected from polyethylene glycol with an MW of 5 kDa - 35 kDa, poloxamer 407, and mixtures thereof.

1.22. Any formulation above wherein the orally acceptable cationic active agent is selected from one or more quaternary ammonium surfactants (such as cetylpyridinium chloride (CPC), biguanidines (such as chlorhexidine bigluconate), cationic amino acids (such as arginine ), metal cations (such as zinc, calcium or stannous ions), or combinations thereof.

1.23. Any of the foregoing compositions wherein an orally acceptable cationic active agent comprises a pyridinium-based surfactant, eg, cetylpyridinium chloride (CPC).

1.24. Any composition above wherein an orally acceptable cationic active agent comprises chlorhexidine.

1.25. Any composition above wherein an orally acceptable cationic active agent comprises arginine.

1.26. Any of the foregoing compositions wherein an orally acceptable cationic active agent comprises zinc ions.

1.27. Any of the foregoing compositions wherein the orally acceptable cationic active agent is an orally acceptable salt selected from zinc salts, stannous salts, pyridinium salts, and biguanide salts.

1.28. Any of the foregoing compositions wherein the orally acceptable cationic active agent is an orally acceptable salt selected from cetylpyridinium chloride and chlorhexidine digluconate.

1.29. Any composition above wherein the orally acceptable cationic active agent is an orally acceptable zinc salt, stannous salt, or a combination thereof.

1.30. Any of the foregoing compositions in which an effective amount of a cationic active agent is present in free or salt form and which provides 0.05 to 0.1% cetylpyridinium chloride, such as about 0.075%.

1.31. Any of the foregoing compositions in which an effective amount of a cationic active agent is present in free or salt form and which provides chlorhexidine digluconate in an amount of 0.1 to 0.2%, for example about 0.12%.

1.32. Any composition above wherein the polyamine, in free or orally acceptable salt form, comprises lysine, in free or orally acceptable salt form.

1.33. Any composition above wherein the stabilizing amount of the polyamine compound is an amount sufficient to substantially affect the interaction between the cationic active agent and the acidic polymer, eg, an amount sufficient to inhibit precipitation or reduce the effectiveness of the cationic active agent.

1.34. Any of the above composition, where the polyamine is lysine in free or salt form, and wherein the composition further comprises glutamic acid, in free or salt form, wherein the total amount of lysine and glutamic acid is 1 to 10%; for example, the combination of lysine and glutamic acid is in a lysine: glutamic acid weight ratio of 3: 1 to 5: 1, where the weight% is calculated based on the weight of free amino acids.

1.35. Any composition above, wherein the composition comprises 1% to 5% lysine, in free or orally acceptable salt form.

1.36. Any composition above, wherein the composition comprises lysine in the form of a hydrochloride salt.

1.37. Any composition above, wherein the composition contains 2% to 4% lysine hydrochloride.

1.38. Any composition above, wherein the composition contains more than 50% water.

1.39. Any composition above, wherein the composition contains 70% to 95% water.

1.40. Any of the above composition, wherein the composition comprises one or more of a thickener, buffer, humectant, surfactant, abrasive, sweetener, flavor, pigment, colorant, anti-caries agent, antibacterial agent, whitening agent, desensitizing agent, preservative or their mixtures.

1.41. Any composition above, wherein the composition comprises a phosphate buffer.

1.42. Any composition above, wherein the composition comprises a buffered solution, wherein the buffered solution comprises sodium hydroxide.

1.43. Any composition above, wherein the composition comprises a humectant.

1.44. Any composition above, wherein the composition comprises a humectant, wherein the humectant is a mixture of glycerin, sorbitol, and propylene glycol.

1.45. Any composition above, wherein the composition comprises an anionic surfactant.

1.46. Any composition above, wherein the composition comprises an anionic surfactant, wherein the anionic surfactant comprises sodium lauryl sulfate.

1.47. Any composition above, wherein the composition comprises an abrasive.

1.48. Any composition above, wherein the composition comprises an abrasive, wherein the abrasive comprises silicon dioxide.

1.49. Any composition above, wherein the composition contains a sweetener.

1.50. Any composition above, wherein the composition comprises a sweetener, wherein the sweetener is sodium saccharin.

1.51. Any composition above, wherein the composition comprises a flavoring agent.

1.52. Any composition above, wherein the composition contains a colorant.

1.53. Any composition above, wherein the composition contains an anti-carious agent.

1.54. Any composition above, wherein the composition comprises a fluoride ion source.

1.55. Any of the foregoing compositions wherein the composition comprises a fluoride ion source, wherein the fluoride ion source is stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, aminofluoride (e.g., N'-octadecyltrimethylenediamine-N, N N'-tris (2-ethanol) dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate and a mixture thereof.

1.56. Any composition above, wherein the composition comprises a whitening agent.

1.57. Any composition above, wherein the composition comprises a whitening agent, wherein the whitening agent is hydrogen peroxide.

1.58. Any of the above composition, wherein the composition contains a desensitizing agent, a vitamin, a preservative, an enzyme, or a mixture thereof.

1.59. Any of the foregoing composition, wherein the composition is an oral rinse, toothpaste, tooth gel, tooth powder, non-abrasive gel, mousse, foam, oral aerosol, lozenge, oral tablet, dental product, or pet care product.

1.60. Any composition above, wherein the composition is an oral rinse.

1.61. Any composition above that is biphasic, for example, where the solution provides two different aqueous phases having different composition and density.

1.62. Any composition above that is biphasic, wherein one phase contains at least 90% of an orally acceptable acidic polymer, an orally acceptable cationic active agent and lysine or polylysine, and the other phase contains at least 90% of an acceptable for use in the oral cavity of a nonionic polymer.

1.63. Any composition above that contains less than 5%, such as less than 2%, hydrophobic ingredients.

1.64. Any composition above that is substantially oil-free other than flavoring agents.

1.65. Any of the above composition with a pH ranging from 5.5 to 8.0.

1.66. Any of the above composition having a pH value ranging from 5.5 to 6.5.

1.67. Any of the above composition further comprising an anionic surfactant.

1.68. Any of the above composition additionally containing sodium lauryl sulfate, for example 0.1-1.5%.

1.69. Any of the above compositions, where

(I) an orally acceptable acidic polymer comprises a mixture of (a) a copolymer of maleic anhydride and methyl vinyl ether in an amount ranging from 0.5 to 1.5%, and (b) a copolymer of phosphate and acrylate in an amount ranging from 0 .5 to 1.5%;

(ii) an orally acceptable non-ionic polymer comprises polyethylene glycol having a molecular weight of 5 kDa to 20 kDa in an amount of 0 to 3% and Poloxamer 407 in an amount of 0 to 1% in a total amount ranging from 1 to 3%;

(iii) an effective amount of an orally acceptable cationic active agent in free form or an orally acceptable salt form provides chlorhexidine in an amount ranging from 0.1 to 0.2%;

(iv) lysine or polylysine, in free or orally acceptable salt form, is lysine, in free or orally acceptable salt form, in an amount ranging from 0.5 to 3%; and

(v) the amount of water is 70-95%;

where the composition optionally additionally contains sodium lauryl sulfate in an amount of 0-1%, for example 0.1-1%;

where all quantities are by weight of the total composition.

[0023] Further claims are the use of lysine or polylysine, in free or orally acceptable salt form, to stabilize an oral composition comprising an orally acceptable acidic polymer, an orally acceptable nonionic polymer and an effective amount of an orally acceptable cationic active agent in free form or an orally acceptable salt form; for example, use in any of the above compositions 1 et seq.

[0024] As used herein, the term "oral compositions" refers to a composition for which the intended use may include oral care, oral hygiene, or oral care, or for which the intended route of use may include administration into the oral cavity. The term "oral composition", therefore, generally excludes compositions that are highly toxic, unpleasant to taste, or otherwise unsuitable for administration to the oral cavity. In some embodiments, the oral care composition is not intended to be intentionally swallowed, but rather is intended to be retained in the oral cavity for a sufficient amount of time to affect the intended utility. The oral compositions disclosed herein can be used for non-human mammals such as companion animals (eg, dogs and cats) as well as humans. In some embodiments, the oral care compositions disclosed herein are used by humans. Compositions for caring for the oral cavity include, for example, a dentifrice and a mouthwash. In some embodiments, the present invention provides oral rinse compositions.

[0025] As used herein, the term "acceptable for use in the oral cavity" refers to a safe and pleasant tasting material at appropriate concentrations for use in an oral care composition such as a mouthwash or dentifrice.

[0026] As used herein, the term "orally acceptable carrier" refers to any carrier medium useful in formulating the oral compositions disclosed herein. An orally acceptable carrier is not hazardous to a mammal in the amount disclosed herein when retained in the oral cavity, without swallowing, for a period sufficient to provide effective interaction with the tooth surface as required herein. Generally, an orally acceptable carrier is not hazardous even if inadvertently swallowed. Suitable orally acceptable carriers include, for example, one or more of the following: water, thickener, buffer solution, humectant, surfactant, abrasive, sweetener, flavor, pigment, colorant, anti-caries, antibacterial, whitening desensitizing agents, vitamins, preservatives, enzymes and mixtures thereof.

[0027] Used in this document, the term "acceptable for use in the oral cavity cationic active agent" means an agent that is cationic in aqueous solution at neutral pH and which provides a certain beneficial effect, such as antimicrobial, anti-gingivitis and / or anti-erosion activity, in against the teeth or mouth. While the agent will generally be in solution in an aqueous formulation, it can be formulated in free form or in an orally acceptable salt form. In certain embodiments, the orally acceptable cationic active agent is selected from one or more of quaternary ammonium surfactants (such as cetylpyridinium chloride (CPC)), biguanides (such as chlorhexidine bigluconate), cationic amino acids (such as arginine), metal cations (such as zinc, calcium or stannous ions), or combinations thereof.

[0028] As used herein, the term "orally acceptable acidic polymer" means an orally acceptable polymer comprising monomers bearing acidic groups, such as carboxyl and / or phosphate groups, for example selected from one or more synthetic anionic linear polycarboxylates and copolymers of phosphate and acrylate. The acidic polymer should have relatively low isoelectric point values, such as a pH value of 5 or less. Suitable molecular weight will vary depending on the particular polymer, the degree of crosslinking or branching and the proportion of acidic functional groups, however, typically the molecular weight is greater than 5000 g / mol. In various embodiments, the acidic polymer can be in a linear or non-linear (i.e. branched) form, or a mixture of linear and branched forms, and the main chain or side chains can include various hydrophobic moieties such as methyl methacrylate monomers, alkane chains, etc. e, and / or uncharged hydrophilic moieties such as PEG or PPG, as well as moieties bearing acidic functional groups. Examples of acidic polymers include synthetic anionic linear polycarboxylates, copolymers of phosphate and acrylate, and combinations thereof, and may be selected from various anionic backbones, including vinyl, acrylic, maleic. The carboxylate moieties along the polymer backbone can be obtained from the monomers themselves, such as in the case of acrylic acid, methacrylic acid or maleic acid, or can be obtained by hydrolysis of the polymer, for example in the case of polybutyl acrylate. The acidic polymer can be composed of copolymers or homopolymers of acidic functional monomers or mixtures thereof.

[0029] As used herein, the term "orally acceptable non-ionic polymer" is a water-soluble polymer that does not participate in ionic forms at appropriate pH values, for example at pH values from 3 to 10, for example, in certain embodiments selected from one or more poly (alkylene oxide) based polymers, for example, selected from polyethylene glycols (PEG), polypropylene glycols (PPG), poloxamers (PEG and PPG block copolymers), random copolymers PEG and PPG, and mixtures thereof. In some embodiments, an orally acceptable nonionic polymer has a molecular weight of at least 3000 Da, such as 6 kDa to 250 kDa. The molecular weight can vary depending on the specific type of polymer, the degree of branching, if any, and the concentration used. Experiments with PEGs having molecular weights ranging from 6 kDa to 35 kDa, for example, have shown that at lower concentrations, such as 3%, in some combination with other ingredients, material with a higher molecular weight 35 kDa was necessary to form a biphasic system, however, in formulations having higher levels of PEG, PEG having a lower molecular weight, for example 6 kDa, can support a biphasic system. In specific embodiments, the nonionic polymer comprises a mixture of (i) a polyethylene glycol (MW 5 kDa-35 kDa) and (ii) a poloxamer (i.e., a block copolymer of ethylene oxide and propylene oxide), for example, poloxamer 407, which is a triblock copolymer, consisting of a central hydrophobic polypropylene glycol block flanked by two hydrophilic polyethylene glycol blocks, where the approximate length of the two PEG blocks is approximately 101 repeating units, while the approximate length of the propylene glycol block is approximately 56 repeating units, commercially available as Pluronic F127 (BASF) ...

[0030] As used herein, the term "polyamine compound" means a molecule having at least two primary or secondary amino groups, for example, having an isoelectric point of pH greater than 8.5, such as pH 9-10. Examples of polyamines include ethylenediamine, lysine, or histidine, and polymers such as lupazole P, which is polyethyleneimine. The polyamine must be safe for its intended use. If the composition is an oral composition, then the polyamine should be acceptable for oral use. The polyamine can be provided in free form or in the form of an acid addition salt. In certain embodiments, the polyamine compound is lysine.

[0031] As used herein, the term "biphasic" refers to stable liquid compositions that include at least two different homogeneous phases with different densities such that the phases are separated at rest. The phases can be easily mixed by shaking, however, they will re-separate within a short period of time, for example less than half an hour. In certain embodiments, the term excludes gels, emulsions, microemulsions, and homogeneous solutions. In certain embodiments, these formulations differ from traditional biphasic formulations in which both phases are aqueous, and not one phase is hydrophobic, but the other is hydrophilic.

[0032] As used herein, the term "isoelectric point" is the pH value in aqueous solution where the molecule is not fully charged. The isoelectric point of lysine, for example, is at pH 9.7 due to its two amines and one carboxylic acid (at this point only one amine is positive and the acid is negative). At every other pH value, Lys contains a certain degree of charge, either overall positive (<pH 9.7, both amines are protonated) or negative (> pH 9.7, both amines are deprotonated - neutral, and the acid group is negatively charged). An acidic polymer, such as either DV8801 or Gantrez S-97, will be the only one to have an isoelectric point with a low pH value of <5, when all carboxylates are protonated, resulting in a total charge of 0. A stabilized system exists between the isoelectric points of the required materials ...

[0033] As used herein, the term "copolymer of phosphate and acrylate" refers to a polymer composed of acrylate monomers and monomers bearing phosphate groups, for example a copolymerized product of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1

where n is 0, 1, or 2. In some embodiments, the phosphate-acrylate copolymer is a copolymerized product of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of Formula 1 containing acrylic acid in a molar percentage of 80-90%, for example about 85%; methacrylic acid in a molar percentage of 5-15%, for example about 11%, and hydroxyethyl methacrylate phosphates of formula 1 in a molar percentage of 2-6%, for example about 4%. In some embodiments, the phosphate-acrylate copolymer has an average molecular weight of 10 to 40 kDa, eg, 20 to 30 kDa. The disclosed copolymers of phosphate and acrylate include commercially available polymers such as DV8801 (Rhodia). The phosphate side group of a phosphate-acrylate copolymer disclosed herein can function as an anchor for the copolymer to accumulate on the tooth surface, thereby forming a physical layer on the tooth surface that can inhibit staining and / or biofilm formation. For example, in a particular embodiment (the embodiment used in the examples below), the phosphate-acrylate copolymer is a random copolymer having a weight average molecular weight of about 20,000 to 30,000 grams per mole, which is the copolymerized product of a mixture of 2-hydroxyethyl methacrylate phosphates, acrylic acid and methacrylic acid in the respective amounts set forth in Table 1 below.

Table 1

Monomer name and structure Weight ratio of monomer (wt%) Monomer molar ratio (molar%)

eleven 4

75 85

fourteen eleven

[0034] As used herein, the term "synthetic anionic linear polycarboxylate" refers to a polymer synthesized using an olefinic or ethylenically unsaturated carboxylic acid that contains an activated carbon-carbon olefinic double bond and at least one carboxyl group. The acid contains an olefinic double bond, which readily undergoes polymerization because it is present in the monomer molecule either at the alpha-beta position relative to the carboxyl group or as part of the terminal methylene group. Such illustrative acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxypropionic, sorbic, alpha-chlorosorbic, cinnamic, beta-styryl acrylic, muconic, itaconic, citraconic, mesoconic, alphacon-glutaconic benzyl acrylic, 2-cyclohexyl acrylic, angelic, umbellic, fumaric, maleic acids and their anhydrides. Various olefinic monomers copolymerizable with such carboxylic monomers include vinyl acetate, vinyl chloride, dimethyl maleate, etc. The synthetic anionic linear polycarboxylate is mainly a hydrocarbon with an optional halogen and a substituent containing O and bonds present, for example, in ester, ether and OH-groups. The copolymers preferably contain sufficient carboxyl salt groups for water solubility. The terms "synthetic" and "linear" do not include known thickening or gelling agents containing carboxymethyl cellulose and other cellulose derivatives and natural gums, nor carbopols, which are characterized by reduced solubility due to cross-linking.

[0035] In some embodiments, a "synthetic anionic linear polycarboxylate" refers to copolymers in a ratio of 1: 4 to 4: 1 of maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer, for example methyl vinyl ether (methoxyethylene), characterized by a molecular weight (MW) ranging from about 30,000 to about 2,500,000; for example copolymers with a ratio of from 1: 4 to 4: 1, for example about 1: 1, methyl vinyl ether and maleic anhydride, where the anhydride is hydrolyzed after copolymerization to give the corresponding acid having a molecular weight (MW) of from about 30,000 to about 1,000,000, for example from about 300,000 to about 800,000, for example sold under the tradename GANTREZ®, for example GANTREZ® S-97 pharmaceutical grade (MW is about 700,000), available from Ashland Specialty Chemicals, Bound Brook, NJ 08805 ...

[0036] As used herein, the term "tartar prevention agent" refers to a compound or mixture of compounds that inhibits the formation of tartar, a mixture of calcium phosphates on an organic matrix, and / or the accumulation of plaque on teeth to form tartar (calculus) ...

[0037] As used herein, the term "chemical stain" refers to discoloration of a tooth surface caused by adsorption or absorption of a colored agent on a surface or surface, or caused by a chemical reaction of a dental surface material (eg, tooth enamel) with a colored or uncolored agent in contact with surface. "Chemical coloration" as used herein means the formation and / or formation of a chemical stain.

[0038] As used herein, the term "dental surface" refers to the surface of a natural tooth or the hard surface of artificial dentition systems, including a crown, dental pulp coating, filling material, bridge, dental implant, etc. In some embodiments the implementation of the tooth surface is a natural tooth.

[0039] The compositions are, for example, oral care compositions according to composition 1 et seq., Eg, mouth rinses. Any of the compositions of Composition 1 et seq. Are suitable for oral care use, and orally acceptable ingredients are provided. In some embodiments, the implementation of the mouthwash according to composition 1 contains an effective amount of an acceptable for use in the oral cavity cationic active agent that is antimicrobial, anti-gingivitis, anti-erosion and / or anti-carious agent, for example, the cationic active agent is selected from one or more of the surface active substances based on quaternary ammonium (such as cetylpyridinium chloride (CPC)), biguanides (such as chlorhexidine bigluconate), cationic amino acids (such as arginine), metal cations (such as zinc, calcium or stannous ions) or combinations thereof. An orally acceptable cationic active agent may be present in an effective amount, for example, an amount to effect antimicrobial, anti-gingivitis, anti-erosion and / or anti-caries action. The exact amount will depend on the particular active agent and condition to be treated or prevented, however, in various embodiments, antimicrobially effective CPC levels in the mouthwash will include amounts ranging from 0.05 to 0.1%, such as about 0.075% ; wherein the antimicrobially effective levels of chlorhexidine digluconate in the mouthwash will include amounts of 0.1-0.2%, such as about 0.12%; however, anti-erosion or antimicrobial levels of metal cations such as zinc (eg zinc citrate or other soluble zinc salts) or stannous (eg stannous fluoride and / or stannous chloride) will be in the range of 100-1500 ppm.

[0040] The composition for caring for the oral cavity used in the present invention contains significant levels of water. The water used in the preparation of commercial oral care compositions must be deionized and free of organic impurities. The amount of water in the compositions includes free water that is added, plus the amount that is added with other materials.

[0041] Mouth rinses often contain significant levels of ethanol, which is often required to solubilize essential oils and to prevent bacterial contamination. High levels of ethanol may be undesirable because, in addition to potential misuse by ingestion, ethanol can aggravate conditions such as xerostomia. Accordingly, in some embodiments, the oral compositions of the present invention are substantially free of ethanol, such as less than 1% ethanol.

[0042] Humectants can increase the viscosity, mouthfeel and sweetness of the product, and can also help keep the product from degradation or microbial contamination. Suitable humectants include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, propylene glycol, and other polyols and mixtures of these humectants. In some cases, sorbitol may be provided in the form of a hydrolyzate of hydrogenated starch in the form of molasses, which contains mainly sorbitol (the product, if the starch is completely hydrolyzed to glucose, then hydrogenated), however, due to incomplete hydrolysis and / or the presence of saccharides other than glucose, may also include other sugar alcohols such as mannitol, maltitol, and long-chain hydrogenated saccharides, and these other sugar alcohols also act as humectants in this case. In some embodiments, humectants are present in an amount ranging from 5% to 30%, such as from 10% to 20%, by weight.

[0043] Flavors for use in the present invention may include extracts or oils from aromatic plants such as peppermint, curly mint, cinnamon, wintergreen and combinations thereof, refrigerants such as menthol, methyl salicylate, and commercially available products such as OptaCool® from Symrise, and sweeteners, which may include polyols (which also act as humectants), saccharin, acesulfame, aspartame, neotame, stevia, and sucralose.

[0044] Additionally, there is provided a method (Method A) of treating and / or preventing chemical stain, plaque and / or calculus from forming on a tooth surface, comprising contacting the tooth surface with any of the previously described oral compositions.

[0045] Additionally provided herein is Method A in accordance with the following.

A.1. Method A, wherein the composition is composition 1, for example 1.1-1.69.

A.2 Method A or A.1, wherein the method is treating chemical stain, dental plaque and / or calculus on the tooth surface.

A.3. Method A.2, wherein the method is treating a chemical stain on a tooth surface.

A.4. Method A.2, wherein the method is treating plaque on a tooth surface.

A.5. Method A.2, wherein the method is the treatment of calculus on a tooth surface.

A.6. Method A or A.1, wherein the method is to prevent the formation of chemical stain, plaque on teeth and / or calculus on the tooth surface.

A.7. Method A.6, wherein the method is to prevent the formation of a chemical stain on the tooth surface.

A.8. Method A.6, wherein the method is to inhibit the formation of plaque on the dental surface.

A.9. Method A.6, wherein the method is preventing the formation of calculus on the dental surface.

A.10. Method A or A.1-A.9, where the tooth surface is a human tooth.

A.11. Method A or A.1-A.10, wherein the composition is brought into contact with the tooth surface during brushing.

A.12. Any of the above method A et seq. Wherein the composition is biphasic and shaken prior to use.

[0046] Additionally, there is provided a method (method B) for treating and / or preventing gum disease, comprising contacting the oral cavity with any of the previously described oral care compositions.

[0047] Additionally, provided herein is Method B as follows.

B.1. Method B, wherein the composition is composition 1, for example 1.1-1.69.

B.2. Method B or B.1, wherein the method is treating gum disease.

B.3. Method B, B.1 or B.2, wherein the gum disease is gingivitis.

B.4. Method B, B.1 or B, wherein the gum disease is periodontitis.

B.5. Method B or B.1, wherein the method is to prevent the onset of gum disease.

B.6. Method B, B.1 or B.5, wherein the gum disease is gingivitis.

B.7. Method B, B.1 or B.5, wherein the gum disease is periodontitis.

B.8. Method B or B.1-B.7, wherein the oral cavity is the human oral cavity.

B.9. Method B or B.1-B.8, wherein the composition is brought into contact with the oral cavity while brushing.

B.10. Any of the above method B et seq. Wherein the composition is biphasic and shaken prior to use.

[0048] Additionally, there is provided a method (Method C) for treating and / or inhibiting halitosis, comprising bringing the oral cavity into contact with any of the previously described oral compositions.

[0049] Additionally provided herein is Method C according to the following.

C.1. Method C, wherein the composition is composition 1, for example 1.1-1.69.

C.2. Method C or C.1, wherein the oral cavity is a human oral cavity.

C.3. Method C, C.1 or C.2, wherein the composition is brought into contact with the oral cavity while brushing.

C.4. Any method C et seq. Above, wherein the composition is biphasic and shaken prior to use.

[001] [0050] Additionally, there is provided a method (Method D) for inhibiting biofilm formation on a tooth surface, comprising contacting the tooth surface with any of the previously described oral care compositions.

[0051] Additionally, provided herein is Method D in accordance with the following.

D.1. Method D, wherein the composition is composition 1, for example 1.1-1.69.

D.2. Method D or D.1, wherein the tooth surface is a human tooth.

D.3. Method D, D.1 or D.2, wherein the composition is brought into contact with the tooth surface while brushing.

D.4, Any method D above and beyond, wherein the formulation is biphasic and shaken prior to use.

[0052] Additionally, there is provided a method (method E) of treating bacteria to prevent them from sticking together and growing into larger colonies in the oral cavity and / or preventing bacteria from sticking together and growing into larger colonies in the oral cavity, comprising bringing the oral cavity into contact with any of the previously described compositions for the care of the oral cavity.

[0053] Additionally provided herein is Method E in accordance with the following.

E.1. Method E, wherein the composition is composition 1, for example 1.1-1.69.

E.2. Method E or E.1, wherein the oral cavity is the human oral cavity.

E.3. Method E, E.1 or E.2, wherein the composition is brought into contact with the oral cavity while brushing.

E.4. Any of the above method E et seq. Wherein the composition is biphasic and shaken prior to use.

[0054] Compositions 1 et seq. Are further provided for use in any of Methods A through E.

[0055] As used herein, the term "hindering" refers to reducing the degree of development of stains that would otherwise form or form some time after treatment. Such obstruction can range from a small but observable or measurable decrease in the degree of manifestation, to completely inhibiting subsequent staining when compared to an untreated or indifferent tooth surface.

[0056] If the tooth surface is substantially free of chemical stains, method A, such as A.1-A.12, is effective in preventing the formation and formation of new chemical stains that may arise, for example, with oral use of tobacco products (including smoking) or drinking tea, coffee, red wine or cola after processing in accordance with the method. In cases where the tooth surface already has some degree of chemical staining, method A, for example A.1-A.12, is effective in preventing further development of the existing stain. In some embodiments, Method A, such as A.1-A.12, can remove, partially or completely, an existing chemical stain as well as inhibit subsequent staining.

EXAMPLES

Example 1 Chlorhexidine and Anti-Stain Polymers

[0057] Chlorhexidine (CHX) mouthwash is very effective in combating gingivitis. However, after CHX adsorption on the tooth surface, after drinking coffee, tea or red wine, stains often appear, mainly as a result of a charge interaction between positively charged CHX and negatively charged stains. This means that whoever uses chlorhexidine must either avoid dark colored foods and beverages, or get used to more yellow and colored teeth.

[0058] Rhodia DV8801 (also sometimes referred to as Mirapol 8801 or DV) is a copolymer of phosphate and acrylate from Solvay that exhibits significant stain control properties and accumulates on the tooth surface when used in oral care products. However, when DV and CHX are combined, the complexes formed by both of them can precipitate both CHX and DV, inactivating both components.

[0059] However, the inventors have found that CHX and DV can be formulated to prevent sedimentation (or to allow the sediment to re-enter solution) by including lysine (Lys), polyethylene glycol (PEG) and low levels of sodium lauryl sulfate. Additionally, a non-ionic surfactant poloxamer 407 can be used to supplement the SLS proportion. Various formulations were tested having the ranges indicated below.

TABLE 2. Test composition

Materials Range (wt%) Chlorhexidine bigluconate 0.12 - 0.2 DV8801 (copolymer of phosphate and acrylate) 0.02-1.0 Gantrez S-97 (copolymer of methyl vinyl ether and maleic anhydride) 0.02-1 Lysine hydrochloride 0.25-1 Sodium lauryl sulfate (anionic surfactant) 0-1 Poloxamer 407 (nonionic surfactant) 0-1 PEG 10K (nonionic surfactant) 0-3 Water in sufficient quantity

[0060] Reducing the degree of manifestation of spots. The staining efficacy of the test formulations was tested against a commercial mouthwash with 0.12% chlorhexidine digluconate (CHX). Figure 1 shows a comparison of the color change (W) of hydroxyapatite (HAP) discs treated with different solutions. Each HAP disc was incubated in purified saliva for 3 hours. At the end of this time, the discs were rinsed with water and then transferred to the indicated solutions for 15 minutes. They were then washed and transferred back to saliva for a few minutes. This process was repeated three times, after which they were subjected to red wine dyeing for 15 minutes and the color change (ΔW) was measured.

[0061] The results are shown below.

TABLE 3. Stain protection with various formulations

Compositions (wt%) Commercial 0.12% CHX 1 DV / 1 S-97/1 Lys 0.12 CHX / 1 DV / 1 S-97/1 Lys / 0.8 SLS 0.12 CHX / 1 DV / 1 S-97/1 Lys / 0.8 SLS / 2 PEG 10K ΔW 33.2 13.4 16.3 4.1

CHX = chlorhexidine bigluconate; DV = DV8801 (copolymer of phosphate and acrylate); S-97 = Gantrez S-97 (copolymer of methyl vinyl ether and maleic anhydride); Lys = lysine hydrochloride; SLS = sodium lauryl sulfate (anionic surfactant); PEG 10K = polyethylene glycol with a molecular weight of approximately 10 kDa (nonionic surfactant).

As expected, discs treated with a commercial chlorhexidine / red wine mouthwash exhibited significant staining. The solution of 1% DV8801, 1% Gantrez S-97 and 1% lysine (second column) did not contain chlorhexidine but contained anti-stain polymers (DV8801 and Gantrez S-97), thus, as expected, the degree of staining was reduced. A solution of 0.12% Chlorhexidine Bigluconate, 1% DV8801, 1% Gantrez S-97, 1% Lysine and 0.8% Sodium Lauryl Sulfate (SLS) showed only slightly more coloration than a formulation with anti-stain polymers alone, demonstrating that anti-staining polymers in combination with lysine can still protect against staining precipitated by chlorhexidine. Finally, the addition of 2% polyethylene glycol to this formulation resulted in very good stain protection, even better than using anti-stain polymers alone.

[0062] Accumulation of chlorhexidine on HAP. The next question is whether chlorhexidine, in combination with anti-staining polymers, can still properly accumulate for efficacy against bacteria. The HAP discs were exposed to solutions 1-6 listed in Table 4, and then extracted with ethanol to determine the level of chlorhexidine that was adsorbed on the surface.

TABLE 4. CHX Accumulation

Solution Composition (wt%) Accumulated on HAP (ppm) 1 Only H ₂ O 0 2 0.12 CHX 21.5 +/- 1.3 3 Commercial mouthwash with 0.12% CHX 12.7 +/- 2.0 4 0.12 CHX / 1 DV / 1 S-97/1 Lys 0 five 0.12 CHX / 1 DV / 1 S-97/1 Lys / 0.8 SLS 26.6 +/- 1.5 6 0.12 CHX / 1 DV / 1 S-97/1 Lys / 0.8 SLS / 2 PEG 10K 16.0 +/- 1.7

[0063] In the presence of either 0.12% chlorhexidine bigluconate or a commercial mouthwash containing 0.12% chlorhexidine bigluconate (solutions 2 and 3), antibacterial effective chlorhexidine levels accumulated. When chlorhexidine digluconate was combined with acidic polymers (DV and Gantrez S-97) and only with Lys (solution 4), no CHX accumulated on the HAP surface, probably because it exists as a precipitate and cannot sufficiently interact with the HAP surface. Adding SLS to samples 5 and 6 brings CHX back into solution and again allows it to accumulate in HAP. Formulation 6 has an accumulation efficiency comparable to the commercial formulation, however, it also exhibits excellent anti-staining properties, which surprisingly provides the ability to maximize both the accumulation of chlorhexidine and the anti-staining efficiency of acidic polymers.

[0064] Killing bacteria. The short 20 second kill test (SIKT) measures the efficacy of various treatment solutions in killing oral pathogens. The fluorescent SIKT uses a Live / Dead BacLight fluorescent viability staining system to measure bacterial permeabilization with single actives or liquid formulations. A mixed species inoculum culture containing Lactobacillus casei, Streptococcus oralis, Actinomyces viscosus, Veillonella parvula and Fusobacterium nucleatum was centrifuged with an optical density of 0.5 at 610 nm. The supernatant was then removed and the remaining plaque resuspended in sterile phosphate buffered saline (PBS). Then 100 μl of this solution was treated with 100 μl of the test sample for 30 or 60 seconds. Immediately after treatment, the exposure was neutralized by the addition of 1.3 ml of sterile neutralizing liquid D / E medium. Then the neutralizing liquid medium was washed out by centrifugation and resuspended in PBS. Then 50 μl of the sample was transferred in triplicate to a 96-well microplate. Then received fluorescent dyes according to the manufacturer's instructions and added to the samples. Then, the fluorescence was measured in a fluorescence plate reader. The data from this analysis are presented as the percentage of bacteria retained viability relative to the control sample treated with PBS.

TABLE 5. SIKT with different formulations

Compositions (wt%) Commercial 0.12% CHX The dead 0.12 CHX / 1 DV 0.12 CHX / 1 DV / 1 S-97/1 Lys / 0.8 SLS / 2 PEG 10K % viable bacteria 34.9 36.3 116.4 36.6

[0065] The sample labeled as "dead" is a sample in which pure ethanol was used as a highly effective bactericide. In this particular example, a commercial mouthwash containing 0.12% chlorhexidine digluconate exhibits similar effects to ethanol. The solution containing 0.12% CHX / 1% DV showed no killing effect on bacteria, possibly due to complexation and precipitation of the active ingredients. In this regard, no killing effect was expected or observed. Sample # 4 exhibited a significant killing effect and was compared with a commercial mouthwash containing 0.12% chlorhexidine bigluconate, indicating a similar high efficacy.

[0066] Since SLS has its own antibacterial effects, the inventors of the present invention conducted a series of control experiments listed in Table 6 using SIKT.

TABLE 6. SIKT with different formulations

Solution no. Composition (wt%) % viable bacteria 1 Commercial 0.12% CHX 25.9 2 2 PEG 10k / 1 DV / 1 S-97 / 0.5 Lys / 0.4 SLS / 0.5 Poloxamer 407 78.1 3 2 PEG 10k / 1 DV / 1 S-97 / 0.5 Lys / 0.4 SLS / 0.5 poloxamer 407 / 0.12 CHX 38.4 4 2 PEG 10k / 1 DV / 1 S-97 / 0.5 Lys / 0.4 SLS / 0.5 poloxamer 407 / 0.2 CHX 38.8 five 1 Poloxamer 407 92.2 6 0.2 SLS 31.0 7 PBS one hundred 8 Dead (ethanol) 28.4

[0067] Compared to control solution 7, a commercial mouthwash with 0.12% CHX provides a significant reduction in viability of up to 25.9%. Solution 6, containing only SLS, also provides a significant pot life reduction of up to 31%. Solution 2 is a complete formulation without CHX for determining the effect of SLS on bacteria. In the absence of CHX, a viability of 78.1% is observed. Adding 0.12 or 0.2% CHX as in solutions 3 and 4 returns the overall solution efficiency to 38.4 and 38.8% pot life, respectively. This indicates that in the presence of the full composition, the SLS effect is masked behind other materials. However, this basic formulation is nonetheless capable of providing effective CHX levels.

[0068] Stabilization with multiply charged particles. The addition of DV to the CHX solution causes immediate precipitation. However, the addition of low levels of surfactants or multiply charged compounds returns both DV and CHX to solution. The table below lists a variety of compounds that contribute to the re-dissolution of DV-CHX, and what the inventors of the present invention found as their lowest effective levels. These solutions are stable between pH 4.9 and 7. The addition of citric acid to lower the pH to <4.9 causes significant precipitation.

TABLE 7. Materials added to a solution containing 0.12 or 0.2 CHX (w / w active substances) and 1.025 DV (w / w active substances)

Material The lowest effective level. Betaine 0.3% for 0.12% CHX
0.3% for 0.2% CHX
(With significant mixing times)

Example 2: Illustrative Formulation of Chlorhexidine and Anti-Staining Polymers Mouthwash

[0069] The composition of the mouthwash was prepared as follows.

TABLE 8. Composition with 2.5 DV / 0.12 CHX / 0.5 SLS; pH adjusted to 6 using citric acid

Material Level % active substances Applied batch level, 270 g Betaine 0.0000% 30.00% 0.000 DV8801 2.5000% 41.00% 16,463 CHX (20%) 0.1200% 20.00% 1,620 Glycerol 7.2000% 100.00% 19,440 Sorbitol 9.6000% 100.00% 25,920 Lemon acid 0.0004% 100.00% 0.001 Propylene glycol 7.0000% 100.00% 18,900 Peppermint oil 0.1000% 100.00% 0.270 H ₂ O 0.0000% 181.99 Total 270,000

PCT FORMULA

1. Composition for the care of the oral cavity containing:

a) an acceptable acidic polymer for use in the oral cavity;

b) an orally acceptable nonionic polymer;

c) an effective amount of an orally acceptable cationic active agent in free form or an orally acceptable salt form;

d) a stabilizing amount of the polyamine compound in free or orally acceptable salt form, and

e) water.

2. The composition of claim 1, wherein the orally acceptable acidic polymer is selected from one or more of synthetic anionic linear polycarboxylates, copolymers of phosphate and acrylate, and combinations thereof.

3. The composition of claim 2, wherein the orally acceptable acidic polymer is selected from the combination

a) copolymers with a ratio of 1: 4 to 4: 1 maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer, for example copolymers of methyl vinyl ether and maleic anhydride, where some or all of the anhydride moieties are hydrolyzed to provide free carboxyl groups, and

b) copolymerized products of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1,

where n is 0, 1, or 2.

4. A composition according to any one of the preceding claims, wherein the orally acceptable nonionic polymer is selected from polyethylene glycols, polypropylene glycols, poloxamers, and mixtures thereof.

5. A composition according to any of the preceding claims, wherein the orally acceptable cationic active agent is selected from one or more of quaternary ammonium surfactants, biguanides, cationic amino acids, metal cations, and combinations thereof.

6. A composition according to any one of the preceding claims, wherein the orally acceptable cationic active agent is an orally acceptable salt selected from zinc salts, stannous salts, chlorhexidine digluconate and cetylpyridinium chloride.

7. A composition according to any of the preceding claims, wherein the cationic active agent acceptable for use in the oral cavity is chlorhexidine digluconate at a concentration of 0.1% -0.2%.

8. A composition according to any of the preceding claims, wherein the polyamine, in free or orally acceptable salt form, is lysine hydrochloride.

9. A composition according to any one of the preceding claims, wherein the composition comprises 70% to 95% water.

10. A composition according to any of the preceding claims, wherein the composition comprises one or more of a thickener, a buffer solution, a humectant, a surfactant, an abrasive, a sweetener, a flavoring agent, a pigment, a coloring agent, an anti-caries agent, an antibacterial agent, a whitening agent, an agent for reducing sensitivity, preservative or mixtures thereof.

11. A composition according to any of the preceding claims, wherein the composition comprises an anionic surfactant.

12. A composition according to any one of the preceding claims, wherein the composition is an oral rinse.

13. A composition according to any one of the preceding claims, which is biphasic, wherein the solution comprises two different aqueous phases having different composition and density.

14. A composition according to any one of the preceding claims, which contains less than 5% hydrophobic ingredients.

15. A composition according to any one of the preceding claims, which is substantially oil-free other than flavoring agents.

16. A composition according to any one of the preceding claims, characterized by a pH in the range of 5.5 to 8.0.

17. A composition according to any one of the preceding claims, wherein there is no distinct precipitate or reaction between an orally acceptable acidic polymer and an orally acceptable cationic active agent after three months of storage at room temperature.

18. Composition according to any of the previous paragraphs, where

a) an orally acceptable acidic polymer comprises a mixture of (a) a copolymer of maleic anhydride and methyl vinyl ether in an amount ranging from 0.5 to 1.5%, and (b) a copolymer of phosphate and acrylate in an amount ranging from 0, 5 to 1.5%;

b) an orally acceptable nonionic polymer comprises polyethylene glycol having a molecular weight of 5 kDa to 20 kDa in an amount of 0 to 3% and Poloxamer 407 in an amount of 0 to 1% in total an amount ranging from 1 to 3%;

c) an effective amount of an orally acceptable cationic active agent, in free form or an orally acceptable salt form, provides chlorhexidine in an amount ranging from 0.1 to 0.2%;

d) the polyamine compound, in free or orally acceptable salt form, is lysine, in free or orally acceptable salt form, in an amount ranging from 0.5 to 3%; and

e) water is present in an amount of 70-95%;

where the composition optionally additionally contains sodium lauryl sulfate in an amount of not more than 1%; and

where all quantities are by weight of the total composition.

Claims (31)

1. Composition for the care of the oral cavity containing: a) an orally acceptable acidic polymer containing the combination of: i) copolymers in a ratio of 1: 4 to 4: 1 maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer, for example copolymers of methyl vinyl ether and maleic anhydride, where some or all of the anhydride moieties are hydrolyzed to provide free carboxylic groups; and ii) copolymerized products of a mixture of acrylic acid, methacrylic acid and 2-hydroxyethyl methacrylate phosphates of formula 1,

where n is 0, 1 or 2; b) an orally acceptable nonionic polymer, wherein the orally acceptable nonionic polymer is selected from polyethylene glycols, polypropylene glycols, poloxamers, and mixtures thereof; c) an effective amount of an orally acceptable cationic active agent in free or orally acceptable salt form, wherein the orally acceptable cationic active agent is selected from one or more of quaternary surfactants ammonium, biguanides, cationic amino acids, metal cations and combinations thereof; d) a stabilizing amount of a polyamine compound in free or orally acceptable salt form, wherein the polyamine is lysine; e) sodium lauryl sulfate and f) water. 2. The composition of claim 1, wherein the orally acceptable cationic active agent is an orally acceptable salt selected from zinc salts, stannous salts, chlorhexidine digluconate and cetylpyridinium chloride. 3. A composition according to any of the preceding claims, wherein the orally acceptable cationic active agent is chlorhexidine bigluconate at a concentration of 0.1% -0.2%. 4. A composition according to any of the preceding claims, wherein the polyamine, in free or orally acceptable salt form, is lysine hydrochloride. 5. A composition according to any of the preceding claims, wherein the composition comprises 70% to 95% water. 6. A composition according to any of the preceding claims, wherein the composition comprises one or more of a thickener, a buffer solution, a humectant, a surfactant, an abrasive, a sweetener, a flavoring agent, a pigment, a coloring agent, an anti-carious agent, an antibacterial agent, a whitening agent, an agent for reducing sensitivity, preservative or mixtures thereof. 7. A composition according to any of the preceding claims, wherein the composition comprises an anionic surfactant. 8. A composition according to any one of the preceding claims, wherein the composition is an oral rinse. 9. A composition according to any one of the preceding claims, which is biphasic, wherein the solution comprises two different aqueous phases having different composition and density. 10. A composition according to any of the preceding claims, which contains less than 5% of hydrophobic ingredients. 11. A composition according to any of the preceding claims, which essentially does not contain oil other than flavoring agents. 12. Composition according to any one of the preceding claims, characterized by a pH value ranging from 5.5 to 8.0. 13. A composition according to any one of the preceding claims, wherein there is no distinct precipitate or reaction between an orally acceptable acidic polymer and an orally acceptable cationic active agent after three months of storage at room temperature. 14. Composition according to any of the previous paragraphs, where a) an orally acceptable acidic polymer comprises a mixture of (a) a copolymer of maleic anhydride and methyl vinyl ether in an amount ranging from 0.5 to 1.5%, and (b) a copolymer of phosphate and acrylate in an amount ranging from 0, 5 to 1.5%; b) an orally acceptable nonionic polymer comprises polyethylene glycol having a molecular weight of 5 kDa to 20 kDa in an amount of 0 to 3% and Poloxamer 407 in an amount of 0 to 1% in total an amount ranging from 1 to 3%; c) an effective amount of an orally acceptable cationic active agent, in free form or an orally acceptable salt form, provides chlorhexidine in an amount ranging from 0.1 to 0.2%; d) the polyamine compound, in free or orally acceptable salt form, is lysine, in free or orally acceptable salt form, in an amount ranging from 0.5 to 3%; and e) water is present in an amount of 70-95%; where the composition optionally additionally contains sodium lauryl sulfate in an amount of not more than 1%; and where all quantities are by weight of the total composition.